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A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers

Authors :
Shi-Yu Yang
Michelle Beavan
Kai-Yin Chau
Jan-Willem Taanman
Anthony H.V. Schapira
Source :
Stem Cell Reports, Vol 8, Iss 3, Pp 728-742 (2017)
Publication Year :
2017
Publisher :
Elsevier, 2017.

Abstract

Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.

Details

Language :
English
ISSN :
22136711
Volume :
8
Issue :
3
Database :
Directory of Open Access Journals
Journal :
Stem Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.0ad61c3a257e44269be48593e4f9ee2b
Document Type :
article
Full Text :
https://doi.org/10.1016/j.stemcr.2017.01.011